N-of-1 Clinical Trials and Precision Medicine for Cancer

Schematic of our approach to N-of-1 cancer clinical trials. Our goal is to identify existing FDA-approved and investigational compounds that could quickly be tested for effectiveness in blocking master regulators responsible for tumor maintenance.

Clinical genetics has become widely used in cancer diagnosis, but it is still limited in its ability to help the majority of people with cancer. Although genome sequencing can tell whether or not a patient’s tumor contains certain known oncogenes, many patients suffer from a disease that does not correspond to a known subtype. And even when oncogenes are known, effective drugs are rarely available to target them. Moreover, cancer genomes mutate quickly, meaning that targeted therapies directed at a single mutation often do not kill all of the cells in a tumor, enabling cancer to return.

As our lab’s research has shown, network-based approaches that identify master regulators of cancer maintenance and progression can reveal points of vulnerability in the cellular machinery of tumor cells. In the past, we have repeatedly showed that identifying master regulators of particular cancer subtypes and targeting these bottlenecks therapeutically can effectively kill tumor cells.

Using systems biology for precision medicine

Recently, we have begun to explore whether master regulator analysis of individual patients’ tumors could potentially offer an effective strategy for more accurately diagnosing and potentially treating disease. In a collaboration that spans basic and clinical research departments at Columbia University Medical Center, we have launched a new kind of clinical trial, called an “N-of-1 trial,” to investigate this hypothesis.

Traditional clinical trials investigate whether a particular diagnostic method or treatment is safe and effective. Typically, a carefully selected group of patients undergoes the same procedure, and doctors measure its effects in comparison to those seen in others who receive the current standard of care.

N-of-1 clinical trials are based on the growing awareness that grouping patients in this way is limited in its ability to address the extreme genetic variability seen in cancer. Conducted in one patient at a time, N-of-1 clinical trials do not begin with a specific treatment in mind, but are exploratory in nature. Using methods for elucidating regulatory networks developed in our lab, Columbia’s N-of-1 clinical trials aim to identify the specific genetic and molecular factors that are essential for cancer’s growth in a single patient. We have good reason to believe that the results of an N-of-1 study can enable a more precise diagnosis than other standard-of-care methods and may even make it possible to predict which personalized therapeutics are most likely to be effective.

Current N-of-1 cancer clinical trials

Columbia University Medical Center is currently recruiting 260 patients to participate in personalized, N-of-1 clinical trials. Tumor types currently under investigation include:

Anaplastic meningioma

Bladder cancer

Colorectal cancer

Gastrointestinal neuroendocrine tumors

Glioblastoma

Gastric adenocarcinoma

Lung adenocarcinoma

Melanoma

Pancreatic adenocarcinoma

Renal cell carcinoma

Soft tissue sarcoma

Stage 4 breast cancer

Squamous cell carcinoma of the head and neck

During the clinical trial, tumor tissue removed from patients undergoes whole genome DNA sequencing and RNA expression analysis. Researchers in our laboratory then analyze this information within the context of models of gene regulation that are specific to that tumor type. This enables us to identify the distinctive master regulators that are required for the cancerous activity in that specific patient’s tumor.

We then search for existing FDA-approved drugs — or drugs currently at advanced stages of clinical testing — that are known to target those master regulators. Suitable drugs are immediately tested on the patient’s tumor sample, either in cell culture or after being implanted into a mouse model (technically called a patient-derived xenograft), to determine if the compound stops tumor growth. If treatment is effective, it may be investigated further in a more traditional clinical trial.

Providing patients with clinical treatment is beyond the scope of this current round of N-of-1 clinical trials, but if actionable information is found for an individual patient, it may be shared with his or her physician.